Parkinson's disease (PD) afflicts roughly 1 in 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have shown that parkinsonism results from the degeneration of the mesencephalic dopaminergic neurons. In PD patients and in primate PD models, the electrical activity of neurons in external globus pallidus (GPe) is abnormal. Unlike neurons from normal animals, GPe neurons in these animals exhibit synchronous, rhythmic burst discharges. It is our working hypothesis that this abnormal activity is attributable to adaptations in intrinsic properties of GPe neurons and their synaptic input following dopamine (DA) depletion. In the last grant period, our work focused on intrinsic properties controlling repetitive firing of GPe and STN neurons. In this upcoming award period, we plan to build upon these studies and those of other program participants to provide a more complete understanding of the mechanisms controlling rhythmic activity and synchrony in GPe neurons. Specifically, a combination of cellular and molecular approaches will be used to address two specific aims that are natural extensions of the aims in the previous grant period. Our first specific aim is to characterize the role of intrinsic, voltage-dependent Na+ and HCN channels in controlling rhythmic activity in identified GPe neurons in normal and dopamine-depleted mice. It is our working hypothesis that Na+/HCN channels are primary determinants of rhythmic discharge in GPe neurons. The molecular, biophysical and pharmacological properties of these channels and their susceptibility to modulation will be characterized using a combination of electrophysiological, biochemical and scRT-PCR approaches in neurons derived from wild-type, transgenic/knockout and dopamine-depleted mice.Our second specific aim is to characterize the role of GABAergic signaling in controlling activity patterning and synchrony in identified GPe neurons in normal and dopamine-depleted mice. Modeling work sponsored by this PPG predicts that diminished intrapallidal and increased striatal GABAergic input to GPe neurons may be a major factor in the emergence ofsynchrony and burst firing. To test this hypothesis, a combination of electrophysiological, pharmacological and scRT-PCR approaches will be used in neurons derived from wild-type, transgenic/knockout and dopamine-depleted mice. The successful attainment of these specific aims should provide much needed information about the properties of normal and dopamine-depleted GPe neurons - placing the neuroscience community in a much better position to devise new and more effective pharmacological and genetic treatments for Parkinson's disease.